Serial Biopsies May Aid Decisions When Cancer Tx Is Failing

Can identify new-onset mutations that can guide treatment selection

Action Points

When therapautic resistance develops to one oncogene inhibitor in cancer patients, repeat biopsy can shed light on the molecular basis for resistance and provide critical molecular information as to whether sequential therapy with a different inhibitor may be effective.

A case report of a patient in the NEJM highlights the clinical usefulness of developing multiple, structurally distinct inhibitors that target the same oncogenic kinase because patients may respond to one while being resistant to another.

Oncology patients who are relapsing on targeted therapies such as crizotinib (Xalkori) or ceritinib (Zykadia) should be considered for biopsy, a case report of a 52-year-old woman with metastatic anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) has suggested.

"When resistance develops to one inhibitor, repeat biopsy can provide critical information as to whether sequential therapy with a different inhibitor may be effective," Alice T. Shaw, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, Mass., and colleagues reported online in the New England Journal of Medicine.

This case is relevant to all patients who have an oncogene-addicted cancer and relapse on targeted therapies, Shaw said in an interview. "Repeat biopsies as patients develop resistance to targeted therapies can not only reveal important insights about the evolution of resistance, but the results can also have immediate clinical implications and help in identifying therapies that are most likely to be effective in overcoming resistance," she told MedPageToday.

While most crizotinib-resistant tumors remain ALK-dependent and are sensitive to more potent second-generation ALK inhibitors such as ceritinib, alectinib (Alecensa), and brigatinib, "resistance invariably develops," noted Shaw and colleagues. Loratinib (PF-06463922), a small-molecule third-generation inhibitor with potency against ALK and all known resistant mutants, is currently in early clinical testing.

Results from this case report -- which documents the molecular basis for resistance to lorlatinib and one patient's resensitization to crizotinib -- also suggests that detailed knowledge of drug targets can be used to design drugs and predict their clinical impact, said the investigators. "These results highlight the clinical usefulness of developing multiple, structurally distinct inhibitors that target the same oncogenic kinase," said Shaw and colleagues. "Our results also highlight ALK L1198F as a novel resistance mechanism in ALK-rearranged NSCLC."

In the case report, a woman with metastatic ALK-rearranged NSCLC had received multiple prior therapies, including crizotinib and ceritinib. After a clinically significant response to first-line therapy with crizotinib, which lasted for 18 months, a CT scan revealed new abdominal lymphadenopathy. Biopsy of an enlarged lymph node revealed a crizotinib-resistant ALK C1156Y mutation and the patient was switched from crizotinib to ceritinib. After 6 months, the patient relapsed again and was put back on crizotinib, but had no response.

She was then enrolled in a phase 1 clinical trial of loratinib. A restaging CT 5 weeks later revealed a 41% reduction in tumor burden but 8 months following this, a CT scan showed worsening of liver metastases.

Loratinib was discontinued when the patient developed nausea and indigestion. Her total bilirubin level was 0.8 mg per deciliter (14 μmol per liter). After hospitalization, a CT scan showed markedly worsening disease with metastatic lesions in the liver as well as splenomegaly and ascites. Although a number of measures were taken, including giving the patient a single dose of low-dose vinorelbine (22.5 mg per square meter of body weight), her condition continued to deteriorate to the point of impending liver failure.

Molecular testing revealed two ALK resistance mutations in the post-lorlatinib tumor: an ALK L1198F mutation in addition to the C1156Y mutation (ALK C1156Y– L1198F), reported Shaw and colleagues. "This acquired L1198F mutation conferred resistance to lorlatinib, but unexpectedly restored sensitivity to crizotinib, a less potent and less selective first-generation inhibitor," they said. "Remarkably, this substitution changes the exact residue used to enhance selectivity of lorlatinib for ALK over other kinases."

Following reinstatement of crizotinib therapy, the patient underwent rapid clinical improvement and resolution of the liver failure, reported Shaw and colleagues.

"Although we cannot rule out the potential role of low-dose vinorelbine, we think that chemotherapy was not the cause of this patient's dramatic clinical recovery," they commented. "This assessment is based on phase III trial data showing a response rate with vinorelbine of 0.8% among patients with previously treated NSCLC and on our cellular, biochemical, and structural data that provide the mechanistic basis for resensitization to crizotinib."

This study was supported by Pfizer, the National Cancer Institute, the National Foundation for Cancer Research, Be a Piece of the Solution, and Lungstrong.

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